Exon/intron boundaries, novel polymorphisms, and association analysis with schizophrenia of the human synaptic vesicle monoamine transporter (SVMT) gene

Abstract

Keywords: synaptic vesicle monoamine transporter (SVMT); polymorphism; exon/intron boundaries; schizophrenia; association studyThe synaptic vesicular monoamine transporter (SVMT), alternatively vesicular monoamine transporter 2 (VMAT2), pumps cytosolic monoamines including dopamine, norepinephrine, serotonin, and histamine into synaptic vesicles. Altered functions of SVMT have been implicated in the pathogensis of several neuropsychiatric diseases. We determined exon/intron boundaries of the human SVMT gene and performed mutational analysis for the exonic and neighboring intronic regions of the gene. Detected polymorphisms were subject to association analysis with schizophrenia in a familybased design. The human SVMT gene consists, of 16 exons and 15 introns, which is consistent with the murine SVMT gene. When mutational analysis was performed by the single strand conformational polymorphism (SSCP) analysis, we found two and four single nucleotide polymorphisms (SNPs) in exons and neighboring introns, respectively. Neither exonic SNP results in an amino acid change. In family-based association analyses in a sample of 50 Japanese schizophrenics and their parents, no significant association was found for the intronic polymorphisms. Our data suggest that there is no common polymorphism in the SVMT gene affecting the primary structure of the human SVMT protein. Furthermore, we obtained no evidence for the major effect of the novel polymorphisms on susceptibility to schizophrenia. Molecular Psychiatry (2001) 6, 456-460.The synaptic vesicular monoamine transporter (SVMT), alternatively vesicular monoamine transporter 2 (VMAT2), pumps cytosolic monoamines including dopamine, norepinephrine, serotonin, and histamine into synaptic vesicles, using the proton gradient maintained across the synaptic vesicular membrane. 1-3 It plays a central role in determining the amount of monoaminergic neurotransmitters packaged in a vesicle to be available for exocytotic release. 4 The transporter is a site of action of important drugs such as reserpine and tetrabenazine, both of which inhibit vesicular amine transport. Reserpine is a useful drug in the treatment of hypertension and schizophrenia; however, high dosages of reserpine frequently produce a syndrome resembling depressive disorder. 5 Several lines of evidence suggest the involvement of the SVMT in the psychostimulant action of amphetamines which induce monoamine efflux from vesicles, 6 resulting in an increased amount of cytoplasmic neurotransmitter, although the mechanism of action remains to be elucidated. The SVMT is also important for sequestering toxins. It modulates susceptibility to N-methyl-4-phenylpyridinium (MPP + ), the active metabolite of the neurotoxin N-methyl-1,2,3,6-tetrahydropyridine (MPTP) that induces Parkinsonism. 7,8 Recent studies on mutant mice lacking the SVMT gene have provided interesting findings. Although homozygotes for the mutated type die shortly after birth, heterozygous mice are viable into adult life and display reduced amphetamine-condition...

Vmat2Heterozygous Mutant Mice Display a Depressive-Like Phenotype

“…ncbi.nlm.nih.gov/projects/SNP) (Surratt et al, 1993;Glatt et al, 2001Glatt et al, , 2006Iwasa et al, 2001;Kunugi et al, 2001;Burman et al, 2004;Lin et al, 2005). To date, SLC18A2 polymorphisms have been examined only within the context of Parkinson's disease (Burman et al, 2004;Glatt et al, 2006), schizophrenia (Kunugi et al, 2001), long QT syndrome (Iwasa et al, 2001), and alcoholism (Lin et al, 2005).…”

Identification of two risk haplotypes for schizophrenia and bipolar disorder in the synaptic vesicle monoamine transporter gene (SVMT)

“…Selection of SNPs was performed according to the SVMT variation described in a previous work by Kunugi et al [2001]. In our study, we aimed to further explore, with those same markers and in a totally independent sample, the putative association of SVMT gene with psychosis.…”

“…Sequences have been detailed elsewhere [Kunugi et al, 2001]. A multiplex PCR was performed to amplify all fragments at a time.…”

“…It consists of 16 exons and 15 introns and presents polymorphic variation. A first Taq I RFLP polymorphism was identified by Surratt et al [1993] and later, Kunugi et al [2001] reported the existence of six new polymorphic markers at SVMT locus: T440G (rs363387), C1368T (rs363411), T1758C (rs363417), T2666C (rs363420), A2683C (rs363343), and A745G (rs363272). Only two of these single nucleotide polymorphisms are located in exonic positions (T440G, C1368T) but none of them result in amino acid change.…”

“…A linkage study conducted in 16 multiplex pedigrees with schizophrenia spectrum disorders [Persico et al, 1995], examined the Taq I RFLP polymorphism finding no evidence for close linkage among those families. More recently, Kunugi et al [2001] performed a family-based association study with three different single nucleotide polymorphisms at SVMT (T1758C, T2666C, A745G) in 50 schizophrenic trios (proband, father, mother). This study also failed to find any evidence for a major effect of SVMT gene on susceptibility to schizophrenia.…”